Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. This platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with different pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are known to play an essential role in the maintenance of hemostasis and in the pathogenesis of arterial thrombosis. Platelet activation has been shown to be enhanced during coronary thrombolysis. This can lead to delayed reperfusion and reocclusion. Clinical studies with aspirin, ticlopidine, and a monoclonal antibody for platelet glycoprotein IIb/IIIa provide biochemical evidence for platelet involvement in unstable angina, early stage acute myocardial infarction, transient ischemic attack, cerebral ischemia, and stroke.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors in one site. Several endogenous agonists, including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A.sub.2 synthetase inhibitors or receptor antagonists, which act against thromboxane A.sub.2 ; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa or IIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. (1991) Cell 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy. Recent studies in man with a monoclonal antibody for GPIIb/IIIa indicate the antithrombotic benefit of a GPIIb/IIIa antagonist.
There is presently a need for a GPIIb/IIIa-specific antiplatelet agent which inhibits the activation and aggregation of platelets in response to any agonist. Such an agent should represent a more efficacious antiplatelet therapy than the currently available agonist-specific platelet inhibitors.
GPIIb/IIIa on unstimulated platelets does not bind soluble proteins, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.
For example, Canadian Patent Application 2,008,311 (Alig et al.) describes carboxamides and sulphonamides of the following formula: EQU R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b --(Y).sub.c --B--Z--COOR
wherein:
A is selected from a radical including phenyl-R.sup.3, pyridyl-R.sup.3, or thiophenyl-R.sup.3 ; PA1 B is selected from a radical including phenyl-R.sup.4, pyridyl-R.sup.4, or thiophenyl-R.sup.4 ; PA1 W is selected from --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.3 --, --CH.sub.2 CH(CH.sub.3)--, --COCH.sub.2 --, --CH(OH)CH.sub.2 --, or --CH.sub.2 COCH.sub.2 --; PA1 X is selected from --CONR.sup.2 --, --NR.sup.2 CO--, --SO.sub.2 NR.sup.2 -- or --NR.sup.2 SO.sub.2 --; PA1 Y is selected from --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 O--, --OCH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.dbd.CH--, etc.; PA1 Z is selected from --OCH.sub.2 --, --NR.sup.6 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 --, --CH.dbd.CH--, or --C(CH.sub.3).dbd.CH--; PA1 R is selected from H, lower alkyl, phenyl or phenyl-lower alkyl; PA1 R.sup.1 is selected from amidino or guanidino; PA1 R.sup.2 is selected from H, lower alkyl, phenyl-lower-alkyl, etc.; PA1 R.sup.3 is selected from H, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or amidino; PA1 R.sup.4 is selected from H, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or a radical --Z--COOR or --CH.dbd.CH--(CH.sub.2).sub.n COOR; PA1 R.sup.6 is selected from H, lower alkyl or benzyl; PA1 n is selected from an integer of 0-4; PA1 a and c denote an integer of 0 or 1; PA1 b is selected from an integer of 0-2, where a and b are 0 when c is 1, and c is 0 when a or b is different from zero. PA1 R.sup.2 and R.sup.3 denote H, aryl, C.sub.1 to C.sub.10 alkyl or cycloalkyl, which may be further substituted; PA1 R.sup.4 is selected from aryl, C.sub.1 to C.sub.10 alkyl, cycloalkyl, aralkyl, alkaryl, alkanoyl, alkylamino, alkoxyalkyl, or carboxyalkyl; PA1 R.sup.5 is selected from a 4 to 8 membered heterocyclic ring with 1-4 heteroatoms, carboxylic acids, esters, or aminoacid linked carboxamides, and prodrugs thereof; PA1 X, Y, Z are optional substituents selected from N, O, S(O).sub.0-2, C.dbd.O, C.dbd.S, CH--OH, CH.dbd.CH, C.tbd.C, a 4 to 8 membered ring with 0-4 heteroatoms, aryl, amide, or sulfonamide; PA1 m, n are selected from an integer from 0 to 10; and PA1 p is selected from an integer from 0 to 3.
These compounds are claimed as medicines for the treatment of thrombosis, apoplexy, myocardial infarction, inflammations, arteriosclerosis, and tumors.
European Patent Application Publication Number 0,478,363,A2 (Laswell et al.) describes sulfonamide fibrinogen IIb/IIIa receptor antagonists of formula: ##STR1## wherein: R.sup.1 is selected from a 4 to 8 membered heterocyclic ring containing 1-4 heteroatoms; amine, amidine, guanidine, quinuclidine, or isoquinuclidine, all of which may be further substituted;
European Patent Application Publication Number 0,478,328 A1 (Egbertson et al.) discloses related fibrinogen receptor antagonists wherein the SO.sub.2 R.sup.4 group of the compounds in EP 0,478,363,A2 is replaced by the R.sup.4 substituent, ##STR2##
wherein R.sup.4 is selected from H, aryl, amino acid with amide linkage, C.sub.1 to C.sub.10 alkyl, cycloalkyl, aralkyl, alkaryl, alkanoyl, alkylamino, alkoxyalkyl, and carboxyalkyl.
None of the above-cited references disclose or suggest the novel compounds of the present invention.
Compounds of the present invention represent novel structures which bind to the glycoprotein IIb/IIIa receptor, thereby preventing fibrinogen from binding at its platelet receptor site, leading to efficacy in the prevention of blood platelet aggregation and subsequent clotting disorders.